A pleiotropic role for exosomes loaded with the amyloid ß precursor protein carboxyl-terminal fragments in the brain of Down syndrome patients.

Down syndrome (DS) is characterized by cognitive deficits throughout the life span and with the development of aging-dependent Alzheimer's type neuropathology, which is related to the triplication of the amyloid ß precursor protein (APP) gene. A dysfunctional endosomal system in neurons is an early characteristic of DS and APP metabolites accumulate in endosomes in DS neurons. We have previously shown enhanced release of exosomes in the brain of DS patients and the mouse model of DS Ts[Rb(12.1716)]2Cje (Ts2), and by DS fibroblasts, as compared with diploid controls. Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from DS and Ts2 brains, and from the culture media of human DS fibroblasts are enriched in APP carboxyl-terminal fragments (APP-CTFs) as compared with diploid controls. Moreover, APP-CTFs levels increase in an age-dependent manner in EVs isolated from the brain of Ts2 mice. The release of APP-CTFs-enriched exosomes may have a pathogenic role by transporting APP-CTFs into naïve neurons and propagating these neurotoxic metabolites, which are also a source of amyloid ß, throughout the brain, but also provides a benefit to DS neurons by shedding APP-CTFs accumulated intracellularly.